DESCRIPTION (Applicant's abstract): The long-range goal in this project is to identify neural mechanisms involved in airway responses to inhaled irritants. Recent studies have shown enhanced neuropeptide and neurotransmitter synthesis after allergic injury or irritant exposure to the airways. There is increasing evidence that cytokines and growth factors released during inflammation in the airways mediate neuronal responses. We propose to study the time course, including up regulation and recovery, of neurotransmitter expression in sensory and intrinsic airway neurons and changes in airway smooth muscle responsiveness after ozone exposure. We will evaluate the role of nerve growth factors and inflammatory cytokines that contribute to the induction, maintenance and recovery of airway neurons and identify mechanisms involved in regulating neuronal and airway responses to inhaled irritants such as ozone. The specific aims are: 1) to establish the time course of neuronal changes and airway function during the initial inflammatory response to and subsequent recovery from single or repeated ozone exposures; 2) to identify specific neural pathways involved in altered airway responses after ozone exposure; 3) to evaluate the airway neuronal, inflammatory and smooth muscle responses to specific cytokines and growth factors, initially IL-1, LIF and NGF; and 4) to identify the role of cytokines and growth factors in regulating neuronal and airway responses to ozone exposure. These experiments will determine mechanisms of neural responses to irritant exposures like ozone and evaluate the role of cytokines and growth factors regulating ozone-induced neurotransmitter expression of intrinsic and sensory airway neurons. Better understanding of neural responses in the airways may lead to new ways of controlling and treating asthma.